One Lobe,Two Pathologies: First Report of an Intrathyroidal Parathyroid Adenoma Invaded by Papillary Thyroid Cancer and Review of the Literature

Abstract

Intrathyroidal parathyroid adenomas (ITPAs) are rare causes of primary hyperparathyroidism, with type III variants, being the rarest. Coexistence of ITPA and papillary thyroid carcinoma (PTC) in the same lobe is exceedingly rare. The pathogenesis of this rare coexistence is unclear, possibly related to embryologic displacement or local microenvironmental factors. No prior reports have documented direct invasion of ITPA by PTC. We report a 63-year-old woman with hypercalcemia and osteopenia. Imaging suggested a right lobe ITPA. Hemithyroidectomy revealed a type II ITPA and multifocal PTC, with histopathology confirming carcinoma invasion into the adenoma. Postoperatively, calcium and PTH normalized. Completion thyroidectomy revealed a contralateral PTC focus, and adjuvant radioactive iodine was planned. Including this case, only 7 reports exist of concurrent ITPA and PTC, primarily in women aged 50 to 70 with right-lobe involvement. Diagnosis is difficult due to imaging overlap with benign nodules; although 99mTc-sestamibi and 4D-CT improve localization, fine-needle aspiration remains limited. This case is the first to document direct PTC invasion of an ITPA and highlights the importance of surgical excision in suspected ITPA, both for definitive treatment and to uncover occult malignancy. This paper aims to present the first reported case of concurrent ITPA and PTC within the same lobe, with histologically confirmed direct carcinoma invasion into the adenoma, review the existing literature on this rare coexistence and highlight the associated diagnostic challenges and surgical considerations.

Introduction

Primary hyperparathyroidism is the third most common endocrine condition, following diabetes and thyroid disorders. Approximately 80% of cases are caused by a single adenoma; while around 15% result from 4-gland hyperplasia. ¹ Intrathyroidal, parathyroid adenomas (ITPAs) are a rare cause of primary hyperparathyroidism, with a reported incidence ranging from 0.7% to 6%. ² ITPAs are classified into 3 types. Type I adenomas are not truly intrathyroidal but are located within the loose tissues surrounding the thyroid, and completely outside the thyroid capsule. Type II adenomas are partially contained within the thyroid gland but still visible on its surface while type III lesions are truly intrathyroidal, entirely embedded within the thyroid parenchyma. The deeper the parathyroid gland is within the thyroid, the rarer the condition, with type III incidence rates reaching 0.7%. ³

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer, diagnosed in 80% to 85% of thyroid malignancies. ⁴ The concurrent occurrence of parathyroid adenoma and PTC is exceptionally rare, with a reported incidence of only 0.2%. ⁵ Even rarer is the coexistence of ITPA and PTC. A literature review of PubMed, Scopus, and EMBASE using the keywords “Intrathyroidal parathyroid adenoma,” “papillary thyroid carcinoma,” “Thyroid cancer,” “parathyroid adenoma” identified only 6 reported cases^6-11 (Table 1). The objective of this paper is to describe the first reported case of concurrent ITPA and PTC within the same lobe, with histologically confirmed direct carcinoma invasion into the adenoma, review the existing literature on this rare coexistence and highlight the associated diagnostic challenges and surgical considerations

Table 1.

Reported Cases from the Literature of Coexisting Intrathyroidal Parathyroid Adenoma and Papillary Thyroid Carcinoma.

Year	Author	Gender	Age (years)	Chief complaint	Investigations	Lobe involved	Lesion size (cm)	Surgery	Adjuvant therapy
2005	GÜREL et al.	F	76	Extremity pain, fatigue	99mTc-pertechnetate scan, 99mTc- MIBI scan, US	RT (PTC), LT (ITPA)	RT: 0.8 (PTC), LT: 1.2 (ITPA)	LT lobectomy, RT subtotal thyroidectomy	None
2009	Qasaimeh et al.	F	53	Polyarthralgia, back pain	99mTc-MIBI scan, US	RT (ITPA, PTC)	RT: 1 (ITPA), 0.9 (PTC)	RT lobectomy, isthmectomy, wide excision of fascia and fat	Completion thyroidectomy, central LND, RAI
2019	Yang et al.	M	53	Incidental thyroid nodules	US, FNAB, 99mTc MIBI scan, SPECT/CT	RT(ITPA), LT (PTC)	RT: 1.2 (ITPA), LT: multifocal PTC	LT inferior parathyroidectomy, thyroid lobectomy, central LND	None
2020	Al Yahri et al.	F	61	Generalized bone ache, polyuria, right neck mass	US, FNAB, 99mTc-MIBI scan, genetic testing (BRAFV600E)	RT (ITPA, PTC)	RT: 2 (ITPA, PTC - hobnail variant)	RT lobectomy	None, follow-up
2022	Guneyli et al.	F	53	Fatigue	US, FNAB	RT (PTC, ITPA), LT (PTC)	RT: 1 (PTC), 1 (ITPA)	TT	None
2024	Skowrońska-Szcześniak et al.	F	30	Incidental osteopenia, hypercalcemia and thyroid nodules	US, FNAB, 99mTc-MIBI Scan	Bilateral PTC, ITPA)	Right: 1.5 (PTC), LT: 2 (ITPA) small foci of PTC	TT, LND	None

Case Presentation

A 63-year-old nonsmoker female with a medical history of dyslipidemia was incidentally found to have hypercalcemia (11.4 mg/dL) in late 2023 during evaluation for acute height loss and osteopenia. She had no history of radiation exposure or prior thyroid surgeries. Subsequent laboratory evaluation in June 2024 confirmed persistent hypercalcemia (11.8 mg/dL), an elevated parathyroid hormone (PTH) level of 126 pg/mL, low phosphorus level of 2.5 mg/dL and normal creatinine levels, raising suspicion for primary hyperparathyroidism.

A Technetium-99m sestamibi scintigraphy revealed nodular radiotracer uptake at the inferior pole of the right thyroid lobe, suggestive of a parathyroid adenoma (Figure 1a). A 4D-CT scan further delineated a well-defined lesion measuring 9 mm × 8 mm × 11 mm and confirmed that the right inferior parathyroid gland was completely embedded within the thyroid parenchyma, consistent with a type II ITPA (Figure 1b).

Figure 1.

(a) Technetium-99m sestamibi scintigraphy demonstrates persistent focal radiotracer uptake at the inferior pole of the right thyroid lobe on delayed images, consistent with a parathyroid adenoma indicated by the red arrow. The early thyroid phase reveals homogeneous uptake throughout the thyroid gland without discrete abnormal foci. (b) Axial and coronal 4D-CT images demonstrate a well-defined intrathyroidal parathyroid adenoma localized to the right lower pole of the thyroid gland, appearing hypodense relative to the surrounding thyroid tissue as indicated by the orange arrow. (c) Gross specimen showing an intrathyroidal parathyroid adenoma completely embedded within thyroid tissue, encircled in yellow. The adenoma is visualized as a reddish-brown, well-circumscribed nodule with a yellowish hue, and required thyroid lobectomy for complete excision. (d) H&E-stained section demonstrating an intrathyroidal parathyroid adenoma partially invaded by papillary thyroid carcinoma. The adenomatous parathyroid tissue, highlighted by a red thick arrow, is sharply contrasted with clusters of malignant thyroid cells, indicated by a green arrow, which exhibit nuclear clearing, grooves, and pseudo-inclusions. Features consistent with classic PTC morphology infiltrating into the parathyroid parenchyma.

The patient underwent a right hemithyroidectomy, during which the right lower parathyroid gland was identified as intrathyroidal, adherent to, and inseparable from the surrounding thyroid tissue (Figure 1c). Intraoperative PTH monitoring demonstrated a greater than 50% reduction after lobectomy completion, decreasing to 20 pg/mL, and confirming successful adenoma excision. The patient tolerated the procedure well, with no postoperative complications.

Histopathological analysis confirmed the presence of an intrathyroidal hypercellular parathyroid gland, consistent with a parathyroid adenoma. Examination of the thyroid tissue revealed multifocal PTC, with the largest focus measuring 7 mm in greatest dimension. Additionally, direct carcinoma invasion into the parathyroid adenoma was observed, a finding not previously reported in the literature. Surgical margins were negative for malignancy, with no carcinoma detected at the resection boundaries (Figure 1d).

Postoperatively, normalization of serum calcium and PTH levels confirmed the resolution of hyperparathyroidism. Given the unexpected multifocal PTC with invasion into the parathyroid adenoma, a completion thyroidectomy was undertaken, which revealed a solitary 3 mm focus of papillary carcinoma. She is scheduled to receive radioactive iodine as adjuvant therapy.

Discussion

Primary hyperparathyroidism (PHPT) varies in presentation, from asymptomatic cases to symptoms like bone pain, kidney stones, and height loss secondary to elevated PTH and calcium levels. ¹ This variability is also seen in patients with ITPA. Among the reported cases, 4 presented with hyperparathyroidism symptoms.^6,7,9,10 Notably, our patient presented with height loss and osteopenia. In contrast, the other 2 cases were incidentally identified thyroid nodules during routine imaging: 1 in a kidney transplant recipient ⁸ and another during follow up for MEN-1 ¹¹

This condition is 3 times more common in females, as demonstrated in our ITPAs cohort, where all 6 out of the 7 patients, including ours, were female.^1,6,7,9,11 It primarily affects individuals aged 50 to 70. In our cohort, 5 of 7 patients were aged 53 to 63 years,^1,7-10 with exceptions being a 76-year-old patient reported by Gurel et al., ⁶ and a 30 year old patient reported by Skowrońska-Szcześniak et al. ¹¹

Embryologically, the superior parathyroid glands migrate briefly from the fourth pouch to the upper thyroid, whereas the inferior parathyroid glands travel a greater distance from the third pouch alongside the thymus. ¹ This longer migration path makes the inferior glands more prone to misplacement and anatomical variation, leading to a higher incidence of adenomas, particularly in ectopic locations, which occur in ~90% of inferior glands mainly in the lateral quadrant.^3,12 It is suggested that the parathyroid gland may become trapped within the thyroid during fusion of the lateral and medial lobes, resulting in an intrathyroidal location. ¹² It is probable that this close proximity to the thyroid may expose it to a rich blood supply and local growth factors, potentially increasing the risk of adenoma formation. Regarding laterality, 5 patients, including ours, had an ITPA in the right lobe,^7-10 consistent with literature findings.^9,13 The reason for right-sided predominance remains unclear. Proposed embryological factors, like asymmetrical parathyroid migration, lack definitive evidence. ¹⁴

Regarding localization, ultrasonography was the primary localization method for all patients.^6-11 Guneyli et al. ¹⁰ described a unique yin-yang pattern on ultrasound. Ultrasound sensitivity for detecting ITPAs varies widely, ranging from 29% to 67%. The resemblance of ITPAs to benign thyroid nodules complicates differentiation, with partial ITPAs being more frequently missed. ²

A 99mTc-sestamibi scan was performed in all 6 cases, accurately localizing the adenoma in each instance, including ours.^6-9,11 Yang et al. ⁸ also used SPECT/CT with sestamibi to enhance localization. 99mTc-sestamibi scintigraphy effectively localizes parathyroid adenomas, ¹ with 60% to 83% sensitivity for ITPAs. False positives may arise from thyroid nodules, while false negatives are associated with small adenomas, multiglandular disease, or normal calcium levels. ² Newer imaging modalities offer improved specificity and resolution. For instance, 11C-methionine PET/CT targets pre-pro-PTH, enhancing parathyroid specificity. Although not specifically studied for IPAs, it has been proven effective in detecting ectopic adenomas in sestamibi-negative cases. ² Similarly, 18 F-fluorocholine PET/CT with its longer half-life and higher spatial resolution compared to 99mTc-MIBI and 11C-methionine, improves detection of small and intrathyroidal adenomas ¹⁵

4D-CT was used in our case only, with limited data on its efficacy in detecting ITPAs. However, existing evidence suggests that it outperforms sestamibi SPECT/CT.^1,16 Bednam et al. evaluated 4D-CT accuracy in distinguishing ITPAs from colloid nodules and PTC. Their findings showed all ITPAs peaked in the arterial phase with significantly higher arterial-to-venous washout, while nodules peaking in the venous or delayed phase were more likely colloid nodules or PTC. ¹⁷

Fine-needle aspiration biopsy (FNAB) was performed in 4 of the 6 cases to diagnose concurrent ITPAs and PTC.^8-11 Although all specimens revealed thyroid pathology, none were diagnostic for ITPAs, which reflects the known limitation of FNAB in this setting. Cytologic interpretation is challenging often due to overlapping features, such as colloid, follicles, and perivacuolar granulation. Parathyroid adenomas can also mimic follicular, papillary, or even medullary thyroid carcinomas. ² To overcome these limitations, recent studies have demonstrated that FNAB combined with PTH washout provides a reliable means of confirming parathyroid tissue, particularly when imaging is negative or discordant. The technique involves ultrasound-guided aspiration with subsequent saline washout of the needle for intact PTH measurement. A washout concentration equal to or higher than the patient’s serum PTH is considered diagnostic, with Castellana et al. reporting a pooled sensitivity of 95% and a PPV of 97%. ¹⁸ Obołończyk et al. further validated this approach, highlighting its practicality and superior sensitivity compared with Tc-99m sestamibi scintigraphy. ¹⁹

The earliest reported association between thyroid and parathyroid disease dates back to 1947. ²⁰ ITPA and PTC rarely coexist. Literature reports indicates that 5 cases, including ours, involved both pathologies in the same lobe.^7,9-11 Some theories suggest a shared oncogenic pathway between thyroid and parathyroid tumors. ²¹ Indicating that an ITPA might obscure an underlying thyroid malignancy, keeping it clinically silent. However, PTC primarily involves BRAFV600E mutations or RET/PTC rearrangements, while parathyroid adenomas are associated with cyclin D1 (PRAD1) or MEN1 mutations, among others.^1,4 An alternative tumorigenesis pathway suggests that the parathyroid tumor microenvironment may influence surrounding thyroid tissue through pressure effects, altered blood flow, or secreted growth factors affecting neighboring cells. Nevertheless, no direct causal link between parathyroid tumors and thyroid carcinoma has been established, and their co-occurrence is considered incidental.^9,22

In terms of management, standardized guidelines for ITPA surgery are lacking, with surgical approaches varying from enucleation to lobectomy or total thyroidectomy. ² The presence of concomitant PTC further complicates surgical decision-making.

Enucleation or minimally invasive thyroid surgery. This approach has proven effective for well-localized adenomas with benign features, particularly when combined with intraoperative localization techniques.^2,21 However, the primary drawback of this approach is the risk of incomplete excision, which may result in persistent hyperparathyroidism and/or missed thyroid malignancy. ²³

Thyroid lobectomy has traditionally been the preferred approach for ITPAs.^2,3,23 This method preserves the contralateral lobe, often maintaining euthyroid function while ensuring complete excision of the ITPA and detecting occult thyroid malignancies, as demonstrated in our case and 2 others in the literature.^6,7 In addition the 2015 American Thyroid Association (ATA) guidelines support lobectomy for localized PTC in many patients, given its low recurrence rates and excellent survival outcomes. ²⁴ However, this approach may be ineffective if the parathyroid adenoma is not well-localized, potentially resulting in a missed diagnosis. ³

Total thyroidectomy is the most aggressive surgical approach and is rarely indicated for isolated ITPA. However, it may be considered if a contralateral thyroid lesion is present^10,11 or, as seen in Qasaimeh et al. ⁷ and our case, when high-risk PTC is identified on pathological examination following an initial lobectomy. This approach aligns with ATA guidelines, enabling postoperative RAI ablation and whole-body scans. ²⁴

Finally, intraoperative PTH monitoring should be performed to confirm complete parathyroid gland removal, as demonstrated in all reported cases.^2,6-11 As in our case, adjuvant RAI should be administered once the criteria are met.^7,24

Conclusion

Intrathyroidal parathyroid adenomas (ITPAs) are rare, and their coexistence with papillary thyroid carcinoma (PTC) is even more uncommon, making diagnosis and management particularly challenging. Accurate identification relies on a combination of biochemical testing and traditional imaging methods such as ultrasound and 99mTc-sestamibi scans. Additionally, 4D-CT demonstrates superior accuracy in distinguishing ITPAs from thyroid pathology. Although rare, clinicians should remain suspicious for the possibility of an underlying malignancy when managing an ITPA to ensure optimal patient outcomes. Surgically, lobectomy is often the most suitable approach, as it effectively addresses both pathologies by ensuring complete removal of the adenoma and detecting an unsuspected malignancy.